OVERALL SUMMARY The long-term goal of this P01 is to develop next generation immunotherapy with chimeric antigen receptor (CAR) T cells and to translate this research into new therapies with curative potential for patients with blood cancer. The CAR developed at our center is now in international trials for refractory/relapsed pre-B cell acute lymphocytic leukemia (ALL). However, multiple myeloma (MM), acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) remain as the major unmet medical need in blood cancers. Our central hypothesis is that therapies with combination of CAR T cells and universal CAR T cells created with CRISPR/Cas9 genetic editing will enable this powerful therapy to reach a broader spectrum of patients with blood cancer. We have brought together a cadre of exceptional investigators from multiple disciplines who have collaborated and published together for many years. Each disease-focused project will be led by a recognized authority in the field. To achieve our goals, we have developed three Projects, which will coordinately closely with essential shared resource cores. In Project 1, we will determine the clinical and immunological impact of treating patients on two clinical trials: (i) CAR T cells targeting CD19 and CD22 will be used to address the remaining unmet medical need in ALL, which is the emergence of CD19 escape variants; and (ii) universal CAR T cells targeting CD19 will be tested in patients with CLL to determine the role of T cell intrinsic resistance to therapy. In AML, the central problem in CAR T cell therapy is the lack of a known surface antigen that is present on AML but lacking from normal hematopoiesis. The goal of Project 2 is to open a wide therapeutic window by genetically modifying normal marrow to make it resistant to killing by anti-AML CAR T cells, and delivering potent anti- leukemic CAR T cells specific for CD33. In Project 3, the overall hypothesis is that anti-myeloma efficacy will be maximized by (i) combining CART-BCMA and CTL019 to eliminate both the dominant neoplastic PC population and rare myeloma-propagating B cells, and (ii) modifying CAR T cells to circumvent specific myeloma-induced T-cell-inhibitory mechanisms (i.e., immune checkpoints). The Cores for this P01 are essential for our progress including provision of project management for collaboration and biostatistics, clinical safety and monitoring, and fiscal support (Core A), a GMP facility for manufacture of cells and RNA (Core B), and a state-of-the-art platform for GLP analysis to provide high dimensional data of the samples generated in all Projects (Core C). The potential for paradigm shifting impact is to transform the lessons of CAR T for ALL into meaningful efficacy against all hematologic malignancies.